TY: THES
T1 - Mechanisms of peripheral tolerance in transplantation
A1 - Graça, Luís, 1971-
N2 - A short-term treatment leading to long-term acceptance of transplanted tissues has been one of the major objectives in transplantation immunology. Non-depleting monoclonal antibodies, such as those targeting CD4, CD8 and CD154, have been shown effective in inducing transplantation tolerance. The cellular and molecular mechanisms that allow tolerance induction and maintenance are still largely unknown. A more precise identification of such mechanisms would allow the development of more robust tolerogenic strategies, and the generation of new diagnostic tools. This thesis demonstrates that transplantation tolerance induced by co-stimulation blockade leads to a dominant and infectious form of tolerance maintained by CD4+ T cells. Co-stimulation blockade, when combined with co-receptor blockade, led to robust tolerance of fully mismatched skin allografts. Such tolerance was also dominant, manifest by linked-suppression and a dependence on regulatory CD4+ T cells. I examined the phenotype of T cells maintaining dominant tolerance, and concluded that these could be found within both the CD4+CD25+ and CD4+CD25- populations of tolerised mice, yet only among the CD4+CD25+ T cells of naïve animals. Such regulatory cells were found not only in the spleen of tolerised mice, but also in the tolerated tissue. Finally, I describe a strategy to eliminate the immunogenicity of 'therapeutic' mAbs by temporarily interfering with their capacity to bind to cells. Further elucidation of mechanisms of transplantation tolerance, namely the identification of specific markers for regulatory T cells, may lead to significant advances on our understanding of T cell suppression and may greatly facilitate the clinical application of tolerogenic strategies.
UR - http://repositorio.ul.pt/handle/10451/1846
Y1 - 2002
PB - No publisher defined